The broad over-reaching goal of this application is to define the role of alcohol abuse in the initiation of chronic pancreatitis and the progression from chronic pancreatitis to pancreatic cancer. It has long been suggested that alcohol abuse plays a role in the etiology of chronic pancreatitis and pancreatic cancer. Evidence to support a role for alcohol abuse in the development of pancreatic cancer is based primarily on two epidemiological observations; chronic alcohol ingestion is associated with other forms of gastrointestinal cancer (stomach, esophageal and liver), and alcohol abuse causes the vast majority of cases of chronic pancreatitis, a disease that confers a significantly increased risk of developing pancreatic cancer. Despite these associations, the role of alcohol consumption in pancreatic disease remains elusive. The molecular basis of alcohol related chronic pancreatitis is poorly understood, and it is still unclear whether alcohol ingestion plays a causative or supporting role in the progression of chronic pancreatitis to pancreatic cancer. Our understanding of the molecular mechanism underlying alcohol related pancreatic disease has been limited by the absence of an accurate experimental model. Recent developments have enabled the generation of improved experimental and genetically based mouse models of chronic pancreatitis and pancreatic cancer. The experiments outlined in this application will make use of these improved models to determine the role that alcohol abuse plays in the etiology and progression of these pancreatic diseases. Pancreatic cancer is a common and lethal malignancy for which there are virtually no therapeutic options. Chronic pancreatitis is an extremely painful, debilitating and intractable disease that confers an increased risk of developing pancreatic cancer. Heavy alcohol intake has been associated with 60-90% of cases of chronic pancreatitis. The lifetime prevalence of alcohol abuse in the United States is 7.7%. Understanding the mechanism by which alcohol abuse predisposes to the development of chronic inflammatory and fibrogenic changes that are seen in chronic pancreatitis, and how alcohol intake influences the progression of chronic pancreatitis to pancreatic cancer is instrumental for the development of treatments for these common, disabling and lethal diseases. [unreadable] [unreadable] [unreadable]